Implementing a novel, multimodal technique for monitoring cerebrovascular hemodynamics in mice as a diagnostic and prognostic tool for single and repeated mild TBI

实施一种新颖的多模式技术来监测小鼠脑血管血流动力学，作为单次和重复轻度 TBI 的诊断和预后工具

基本信息

批准号：
10056044
负责人：
KATHRYN E SAATMAN
金额：
$ 42.08万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2023-05-31
项目状态：
已结题

项目摘要

Project Summary Traumatic brain injuries (TBIs) are a major societal and public health concern with over 2.8 million TBIs reported each year in the US. Mild TBIs (mTBIs), accounting for over 80% of TBIs, can be difficult to diagnose. Because no FDA-approved therapeutic intervention for mTBI exists, a period of rest to allow symptom resolution is the primary treatment approach. It is imperative that while symptomatic, a person recovering from mTBI avoid sustaining a second mTBI, as multiple mTBIs greatly increases the risk for prolonged disability. The period of brain vulnerability after mTBI, however, extends beyond the resolution of clinical symptoms, underscoring the vital need for accurate assessment of neurophysiological recovery in order to mitigate the risks associated with repeated head injury. Unlike moderate and severe TBI, which are typically associated with neuron death and vascular disruption, mTBI results in more subtle physiological and cellular changes, such as metabolic distress and alterations in cerebral blood flow (CBF). We hypothesize that mTBI induces acute, transient changes in CBF that, coupled with metabolic dysregulation, form the basis of the window of vulnerability to repeated mTBI. We predict, therefore, that a second injury induced during the period of acute CBF alteration will result in worsened outcome as reflected by greater perturbations in CBF and metabolism. Our group has developed a novel multiple-wavelength speckle contrast diffuse correlation tomography (MW- scDCT) technique that yields non-invasive, longitudinal, regional mapping of CBF and oxygenation in mice. We have validated our technique against established methods and demonstrated its utility in detecting CBF changes in rodents. In Aim 1, we will first use MW-scDCT to measure cortical and hippocampal CBF and oxygenation after single closed head injury (CHI) to monitor temporal changes and determine the time to recovery. We will then determine whether normalization of CBF is required to prevent synergistic effects of a second CHI on cerebral hemodynamics. Neurovascular coupling and cerebrovascular reactivity will be assessed at selected time points to inform potential mechanisms underlying CBF changes. Finally, quantitative analysis of cerebrovascular structure and communication will be performed to identify anatomical plasticity or damage. In Aim 2, a targeted metabolomics approach will be used to identify metabolite profiles in cortical tissue and plasma which are unique to mice with single or repeated mTBI. We will further test whether restoration of the metabolome coincides with normalization of CBF after mTBI. Such a finding would support a dual-pronged approach for assessing concussion recovery through noninvasive CBF monitoring and assessment of plasma metabolite biomarkers. These studies will pair metabolomics with our innovative MW- scDCT technique for monitoring cerebral hemodynamics to provide new insights into the neurophysiological determinants of the brain’s vulnerability to repeated mTBI and support the development of diagnostic and prognostic biomarkers for mTBI.

项目概要创伤性脑损伤 (TBI) 是一个重大的社会和公共卫生问题，有超过 280 万例 TBI 美国每年都会报告轻度 TBI（mTBI），占 TBI 的 80% 以上，可能很难诊断。由于尚无 FDA 批准的 mTBI 治疗干预措施，因此需要休息一段时间以缓解症状解决是主要的治疗方法，当患者出现症状时，必须从症状中恢复过来。 mTBI 避免维持第二次 mTBI，因为多次 mTBI 会大大增加长期残疾的风险。然而，mTBI 后大脑的脆弱期超出了临床症状的解决范围，强调准确评估神经生理恢复的迫切需要，以减轻与重复性头部损伤相关的风险与通常与中度和重度 TBI 相关的风险不同。随着神经元死亡和血管破坏，mTBI 会导致更微妙的生理和细胞变化，例如代谢窘迫和脑血流量 (CBF) 的改变我们研究了 mTBI 诱发的情况。 CBF 的急性、短暂变化，加上代谢失调，形成了窗口期的基础因此，我们预测，在急性期会诱发第二次损伤。 CBF 的改变将导致结果恶化，这反映在 CBF 和新陈代谢的更大扰动上。我们课题组开发了一种新型的多波长散斑对比漫相关断层扫描（MW- scDCT）技术可产生小鼠 CBF 和氧合的非侵入性、纵向、区域图。已根据既定方法验证了我们的技术，并证明了其在检测 CBF 方面的实用性在目标 1 中，我们将首先使用 MW-scDCT 测量皮质和海马 CBF 和单次闭合性颅脑损伤 (CHI) 后的氧合监测时间变化并确定恢复时间然后我们将确定是否需要 CBF 正常化以防止协同效应。第二个 CHI 对脑血流动力学的影响将是神经血管耦合和脑血管反应性。最后，在选定的时间点进行评估，以了解 CBF 变化的潜在机制。将进行脑血管结构和通讯的定量分析，以确定解剖学在目标 2 中，将使用有针对性的代谢组学方法来识别代谢物谱。皮质组织和血浆是单次或重复 mTBI 小鼠特有的，我们将进一步测试是否如此。代谢组的恢复与 mTBI 后 CBF 的正常化同时发生，这一发现支持了这一观点。通过无创 CBF 监测和评估脑震荡恢复情况的双管齐下的方法这些研究将代谢组学与我们创新的 MW- 相结合。 scDCT 技术用于监测脑血流动力学，为神经生理学提供新见解大脑易受反复 mTBI 影响的决定因素，并支持诊断和治疗的发展 mTBI 的预后生物标志物。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Extraction of tissue optical property and blood flow from speckle contrast diffuse correlation tomography (scDCT) measurements.

从散斑对比漫相关断层扫描 (scDCT) 测量中提取组织光学特性和血流。

DOI：
10.1364/boe.429890
发表时间：
2021-09-01
期刊：
Biomedical optics express
影响因子：
3.4
作者：
Mingjun Zhao;Chong Huang;S. Mazdeyasna;Guoqiang Yu
通讯作者：
Guoqiang Yu

Differential Leukocyte and Platelet Profiles in Distinct Models of Traumatic Brain Injury.

不同脑损伤模型中白细胞和血小板特征的差异。

DOI：
发表时间：
2021-02-26
期刊：
影响因子：
6
作者：
Hubbard, William Brad;Banerjee, Meenakshi;Vekaria, Hemendra;Prakhya, Kanakanagavalli Shravani;Joshi, Smita;Wang, Qing Jun;Saatman, Kathryn E;Whiteheart, Sidney W;Sullivan, Patrick G
通讯作者：
Sullivan, Patrick G

Simultaneous measurements of tissue blood flow and oxygenation using a wearable fiber-free optical sensor.

使用可穿戴无光纤光学传感器同时测量组织血流量和氧合。

DOI：
发表时间：
2021
期刊：
影响因子：
3.5
作者：
Liu, Xuhui;Gu, Yutong;Huang, Chong;Zhao, Mingjun;Cheng, Yanda;Abu Jawdeh, Elie G;Bada, Henrietta S;Chen, Lei;Yu, Guoqiang
通讯作者：
Yu, Guoqiang

Speckle contrast diffuse correlation tomography of cerebral blood flow in perinatal disease model of neonatal piglets.

新生仔猪围产期疾病模型脑血流的散斑对比弥散相关断层扫描。

DOI：
发表时间：
2021-04
期刊：
影响因子：
0
作者：
Huang, Chong;Mazdeyasna, Siavash;Mohtasebi, Mehrana;Saatman, Kathryn E;Cheng, Qiang;Yu, Guoqiang;Chen, Lei
通讯作者：
Chen, Lei

Tissue factor release following traumatic brain injury drives thrombin generation.

创伤性脑损伤后组织因子的释放驱动凝血酶的产生。